U.S. patent application number 11/717980 was filed with the patent office on 2007-09-20 for sustained release matrix pharmaceutical composition.
This patent application is currently assigned to Glenmark Pharmaceuticals Limited. Invention is credited to Abhaykumar M. Chandak, Anandi Krishnan, Amit Mukharya.
Application Number | 20070218135 11/717980 |
Document ID | / |
Family ID | 38518130 |
Filed Date | 2007-09-20 |
United States Patent
Application |
20070218135 |
Kind Code |
A1 |
Mukharya; Amit ; et
al. |
September 20, 2007 |
Sustained release matrix pharmaceutical composition
Abstract
A sustained release pharmaceutical composition in solid dosage
form is provided comprising (a) a therapeutically effective amount
of one or more active pharmaceutical agents; (b) a first high
viscosity release retarding cellulose ether; and (c) a second high
viscosity release retarding cellulose ether, wherein the first and
second high viscosity release retarding cellulose ethers are of the
same material.
Inventors: |
Mukharya; Amit; (Colaba,
IN) ; Chandak; Abhaykumar M.; (Airoli, IN) ;
Krishnan; Anandi; (Vashi, IN) |
Correspondence
Address: |
M. CARMEN & ASSOCIATES, PLLC
170 OLD COUNTRY ROAD
SUITE 400
MINEOLA
NY
11501
US
|
Assignee: |
Glenmark Pharmaceuticals
Limited
Mumbai
IN
|
Family ID: |
38518130 |
Appl. No.: |
11/717980 |
Filed: |
March 14, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60832379 |
Jul 21, 2006 |
|
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|
Current U.S.
Class: |
424/471 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 9/2054 20130101 |
Class at
Publication: |
424/471 |
International
Class: |
A61K 9/24 20060101
A61K009/24 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 14, 2006 |
IN |
366/MUM/2006 |
Claims
1. A sustained release pharmaceutical composition in solid dosage
form comprising (a) a therapeutically effective amount of one or
more active pharmaceutical ingredients; (b) a first high viscosity
release retarding cellulose ether; and (c) a second high viscosity
release retarding cellulose ether, wherein the first and second
high viscosity release retarding cellulose ethers are of the same
material.
2. The composition of claim 1, wherein the active pharmaceutical
ingredient is selected from the group consisting of alprazolam,
acetazolamide and mixtures thereof.
3. The composition of claim 1, wherein the first and second high
viscosity release retarding cellulose ethers have a viscosity of
greater than about 400 centipoise (cP).
4. The composition of claim 1, wherein the first and second high
viscosity release retarding cellulose ethers have a viscosity of at
least about 1500 cP.
5. The composition of claim 1, wherein the first and second high
viscosity release retarding cellulose ethers have a viscosity of at
least about 4000 cP.
6. The composition of claim 1, wherein the first high viscosity
release retarding cellulose ether has a viscosity greater than or
equal to about 1000 cP and the second high viscosity release
retarding cellulose ether has a viscosity greater than or equal to
about 5000 cP.
7. The composition of claim 1, wherein the first high viscosity
release retarding cellulose ether has a viscosity greater than or
equal to about 3500 cP and the second high viscosity release
retarding cellulose ether has a viscosity greater than or equal to
about 10,000 cP.
8. The composition of claim 1, wherein the first high viscosity
release retarding cellulose ether has a viscosity greater than or
equal to about 4000 cP and the second high viscosity release
retarding cellulose ether has a viscosity greater than or equal to
about 15,000 cP.
9. The composition of claim 1, wherein the first and second high
viscosity release retarding cellulose ethers are selected from the
group consisting of a hydroxypropyl methylcellulose (HPMC) polymer,
hydroxypropyl cellulose (HPC) polymer, hydroxyethyl cellulose (HEC)
polymer and mixtures thereof.
10. The composition of claim 1, wherein the first and second high
viscosity release retarding cellulose ethers are a HPMC
polymer.
11. The composition of claim 10, wherein the first and second high
viscosity HPMC are of a type selected from the group consisting of
2208, 2906 and 2910.
12. The composition of claim 10, wherein the first high viscosity
HPMC is of type 2208 and the second high viscosity HPMC is of type
2910.
13. The composition of claim 10, wherein the first high viscosity
HPMC is of type 2208 and the second high viscosity HPMC is of type
2910 and the viscosity of the first and second high viscosity HPMC
is the same.
14. The composition of claim 10, wherein the first high viscosity
HPMC is of type 2208 and the second high viscosity HPMC is of type
2910 and the viscosity of the first and second high viscosity HPMC
is different.
15. The composition of claim 1, wherein the first high viscosity
release retarding cellulose ether is HPMC of type 2208 and the
second high viscosity release retarding cellulose ether is HPMC of
type 2910 and the viscosity of the first and second high viscosity
HPMC is the same.
16. The composition of claim 1, wherein the amount of the first
high viscosity release retarding cellulose ether is about 15 to
about 35 weight percent and the amount of the second high viscosity
release retarding cellulose ether is about 5 to about 20 weight
percent.
17. The composition of claim 1, further comprising one or more
pharmaceutically acceptable excipients.
18. The composition of claim 1, in the form of a tablet.
19. The composition of claim 18, having a total tablet weight of
about 200 mg to about 500 mg.
20. A method of treating a CNS condition or disorder in a subject,
the method comprising orally administering to the subject a
therapeutically effective amount of the composition of claim 1.
Description
PRIORITY
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119 to U.S. Provisional Application No. 60/832,379, filed on
Jul. 21, 2006, and entitled "PHARMACEUTICAL SUSTAINED RELEASE
MATRIX COMPOSITION" and to Indian Provisional Application No.
366/MUM/2006, filed on Mar. 14, 2006, and entitled "PHARMACEUTICAL
SUSTAINED RELEASE MATRIX COMPOSITION", the contents of each of
which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The present invention generally relates to a sustained
release pharmaceutical compositions containing an active
pharmaceutical ingredient such as alprazolam.
[0004] 2. Description of Related Art
[0005] Alprazolam, also known as
8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-.alpha.][1,4]benzodiazepine,
is a member of the 1,4-benzodiazepine class and can be represented
by the structure of Formula I: ##STR1## Alprazolam is marketed in
an extended release tablet form under the tradename Xanax XR.RTM..
Xanax XR.RTM. is indicated for the treatment of panic disorder with
or without agoraphobia. See, e.g., The Merck Index, Thirteenth
Edition, 2001, p. 310-11, monograph 310; and Physician's Desk
Reference, "Xanax XR", 60th Edition, pp. 2655-2659 (2005).
[0006] Acetazolamide, also known as
N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide, can be represented
by the structure of Formula II: ##STR2## Acetazolamide is an
inhibitor of the enzyme carbonic anhydrase. Acetazolamide is
indicated for the adjunctive treatment of: edema due to congestive
heart failure; drug-induced edema; centrencephalic epilepsies
(petit mal, unlocalized seizures); chronic simple (open-angle)
glaucoma, secondary glaucoma and preoperatively in acute
angle-closure glaucoma where delay of surgery is desired to lower
intraocular pressure. Acetazolamide is marketed under the trade
name Diamox.RTM.. See, e.g., The Merck Index, Thirteenth Edition,
2001, p. 11, monograph 54.
[0007] Sustained-release alprazolam formulations have been
investigated, including formulations wherein alprazolam is
dispersed in a polymer matrix, for example, a
hydroxypropylmethylcellulose (HPMC) matrix. Franz et al. (1987),
Journal of Controlled Release 5, 159-172, examined effects of
several formulation variables on in vitro alprazolam release rate
from such a matrix formulation comprising HPMCs of different
viscosity grades, sodium carboxymethylcellulose (sodium CMC) and
lactose. These variables included ratio of high to low viscosity
HPMC, ratio of sodium CMC to lactose, and matrix drug loading.
Franz et al. established relationships among these variables, but
failed to provide guidance on absolute amounts of HPMC to be
formulated with desired amounts of alprazolam.
[0008] U.S. Patent Application Publication No. 20040006072 ("the
'072 application") discloses a sustained release pharmaceutical
composition in a form of a tablet of alprazolam containing a high
viscosity HPMC and a low viscosity HPMC, wherein the total weight
of HPMC in the composition varies from 110 mg to 135 mg per tablet.
The '072 application further discloses that the high and low
viscosity HPMCs were used in a weight ratio of about 40:60 to about
60:40. The high viscosity HPMC used in the '072 application has a
viscosity of about 3000 to about 5600 cP whereas the low viscosity
HPMC has a viscosity of about 2 to about 400 cP, when measured in a
2% aqueous solution at 20.degree. C.
[0009] The prior art reveals that considerable efforts have been
made to develop a sustained release composition of alprazolam,
using a blend of low viscosity HPMC and high viscosity HPMC.
However, there remains a need for improved sustained release
compositions of active pharmaceutical ingredients such as
alprazolam.
SUMMARY OF THE INVENTION
[0010] In accordance with one embodiment of the present invention,
a sustained release pharmaceutical composition in solid dosage form
is provided comprising (a) a therapeutically effective amount of
one or more active pharmaceutical ingredients; (b) a first high
viscosity release retarding cellulose ether; and (c) a second high
viscosity release retarding cellulose ether, wherein the first and
second high viscosity release retarding cellulose ethers are of the
same material.
[0011] In accordance with a second embodiment of the present
invention, a sustained release pharmaceutical composition in solid
dosage form is provided comprising a therapeutically effective
amount of one or more active pharmaceutical ingredients dispersed
in a matrix comprising (a) a first high viscosity release retarding
cellulose ether; and (b) a second high viscosity release retarding
cellulose ether, wherein the first and second high viscosity
release retarding cellulose ethers are of the same material and the
viscosity of the first high viscosity release retarding cellulose
ether is different than the viscosity of the second high viscosity
release retarding cellulose ether.
[0012] In accordance with a third embodiment of the present
invention, a sustained release pharmaceutical composition in solid
dosage form is provided comprising (a) a therapeutically effective
amount of one or more active pharmaceutical ingredients; (b) a
first high viscosity hydroxypropyl methylcellulose (HPMC); and (c)
a second high viscosity HPMC.
[0013] In accordance with a fourth embodiment of the present
invention, a method of treating a CNS condition or disorder in a
subject is provided, the method comprising orally administering to
the subject a therapeutically effective amount of a sustained
release pharmaceutical composition in solid dosage form is provided
comprising (a) a therapeutically effective amount of one or more
active pharmaceutical ingredients; (b) a first high viscosity
release retarding cellulose ether; and (c) a second high viscosity
release retarding cellulose ether, wherein the first and second
high viscosity release retarding cellulose ethers are of the same
material.
DETAILED DESCRIPTION OF THE PREFERED EMBODIMENTS
[0014] The present invention is directed to a sustained release
pharmaceutical composition in solid dosage form which includes a
therapeutically effective amount of one or more active
pharmaceutical ingredients and at least two high viscosity high
viscosity release retarding cellulose ethers of the same release
retarding material.
[0015] Suitable active pharmaceutical ingredients for use in the
compositions of the present invention include, but are not limited
to, alprazolam, acetazolamide and the like and mixtures thereof.
Illustrative methods for preparation of alprazolam,
8-chloro-1-methyl-6-phenyl-4H-s-triazolo-[4,3-.alpha.]-1,4-benzodiazepine
(I), are known and disclosed in, for example, U.S. Pat. Nos.
3,709,898; 3,879,413; 3,980,789; and 3,987,052, the contents of
which are incorporated by reference herein. Any pharmaceutically
acceptable form of alprazolam or acetazolamide can be used,
including any suitable crystalline or other solid state form,
enantiomer or tautomer thereof.
[0016] In the pharmaceutical composition in solid dosage forms of
the present invention such as a tablet, the active pharmaceutical
ingredient such as alprazolam can be present in an amount of about
0.1 mg to about 5 mg, preferably about 0.5 to about 3 mg, for
example about 0.5 mg, about 1 mg, about 2 mg or about 3 mg. In one
embodiment, the weight for all the quantities of the solid dosage
form, i.e., a total solid dosage form (e.g., tablet) weight, can
range from about 200 mg to about 500 mg, preferably from about 300
mg to about 400 mg. with 300 mg being most preferred.
[0017] The active pharmaceutical ingredient(s) is distributed in a
matrix that comprises at least a first high viscosity release
retarding cellulose ether and a second high viscosity release
retarding cellulose ether, wherein the first and second high
viscosity release retarding cellulose ethers are of the same
material. In one embodiment, the viscosity of the first high
viscosity release retarding cellulose ether is different than the
viscosity of the second high viscosity release retarding cellulose
ether. In another embodiment, the viscosity of the first high
viscosity release retarding cellulose ether is the same as the
viscosity of the second high viscosity release retarding cellulose
ether and wherein the substitution type of each of the cellulose
ether is different. The term "high viscosity release retarding
cellulose ethers" as used herein are those cellulose ethers which
tend to slow down or retard or delays the release of the active
ingredient after administration and have a viscosity greater than
about 400 centipoise (cP) and preferably at least about 1500 cP and
most preferably at least about 4000 cP as measured in a 2% aqueous
solution at 20.degree. C. In one embodiment, the first high
viscosity release retarding cellulose ether can have a viscosity
greater than or equal to about 1000 cP and the second high
viscosity release retarding cellulose ether can have a viscosity
greater than or equal to about 5000 cP. In a second embodiment, the
first high viscosity release retarding cellulose ether can have a
viscosity greater than or equal to about 3500 cP and the second
high viscosity release retarding cellulose ether can have a
viscosity greater than or equal to about 10,000 cP. In a third
embodiment, the first high viscosity release retarding cellulose
ether can have a viscosity greater than or equal to about 4000 cP
and the second high viscosity release retarding cellulose ether can
have a viscosity greater than or equal to about 15,000 cP.
[0018] Suitable release retarding cellulose ethers for use in the
compositions of the present invention include, but are not limited
to, hydroxypropyl methylcellulose (HPMC) polymers, hydroxypropyl
cellulose (HPC) polymers, hydroxyethyl cellulose (HEC) polymers,
and the like. Preferably, the first and second release retarding
cellulose ethers are a HPMC polymers. They are all commercially
available in a wide variety of viscosity grades.
[0019] HPMC polymers are commercially available in different
viscosity grades, under several trade names, including
Methocel.RTM. E, F, J and K of Dow Chemical Co., U.S.A., HPM of
British Celanese Ltd., U.K., and Metalose.RTM. of Shin-Etsu Ltd.,
Japan. The various grades available under a given trade name
typically represent differences in methoxy and hydroxypropoxy
content as well as molecular weight of the HPMC. The cellulose
ethers routinely used in pharmaceutical industry for sustained
release matrix compositions, differ with respect to the solubility,
viscosity, gelling strength and hydration rate. The selection of a
desired grade of a cellulose ether is based on the aforementioned
properties of the cellulose ether and characteristics of the active
ingredient. The viscosity of HPMC polymers affects hydration speed
in the initial stage of the exposure to the dissolution medium and
the gel strength or erosion rate of the gel in the subsequent
stages of exposure.
[0020] The high viscosity grades of HPMC polymers in the
composition of the present invention are available in various
substitution types. The substitution type of HPMC polymers affects
hydration speed of HPMC particles and gel strength, which can
influence the dissolution profile. The term "high viscosity HPMC"
herein refers to HPMC having a viscosity of about 1,500 to about
225,000 cP. Representative high viscosity HPMCs of various
substitution types for use herein include HPMC 2208, HPMC 2910, and
HPMC 2906. A high viscosity HPMC 2208 can have a viscosity of about
3000 to about 5600 cP (e.g., available as Methocel.RTM. K4 MP of
Dow) or a viscosity of about 11,250 to about 21,000 cP (e.g.,
available as Methocel.RTM. K15M of Dow) and contains about 19% to
about 24% by weight of methoxyl substituents, and about 7% to about
12% by weight of hydroxypropoxyl substituents. HPMC 2910 can have a
viscosity of about 3000 to about 5600 cP (e.g., available as
Methocel.RTM. E4M of Dow) and contains about 28% to about 30% by
weight of methoxyl substituents, and about 7% to about 12% by
weight of hydroxypropoxyl substituents. HPMC 2906 can have a
viscosity of about 3000 to about 5600 cP (e.g., available as
Methocel.RTM. F4M of Dow) and contains about 27% to about 30% by
weight of methoxyl substituents, and about 4% to about 7.5% by
weight of hydroxypropoxyl substituents.
[0021] In one embodiment of the present invention, the two
different high viscosity HPMC polymers are about 4000 cP and about
15000 cP wherein the HPMC is the same or different substitution
type. In a preferred embodiment of the present invention, the two
different high viscosities HPMCs are 4000 cP and 15000 cP wherein
the substitution types are 2208 and 2910, respectively. In another
embodiment, the two different high viscosity HPMC polymers can have
the same viscosity and be of a different substitution type as
exemplified in Example 3.
[0022] In one embodiment, a sustained release matrix composition of
the present invention comprises two different high viscosity grades
HPMC polymers, wherein the viscosity of both the grades, is not
less than about 400 cp, preferably not less than about 1500 cp
(centipoise), more preferably not less than about 4000 cp. The two
different high viscosity grades of HPMC may belong to the same or
different substitution types.
[0023] Generally, the first high viscosity release retarding
cellulose ether can be present in the solid dosage forms of the
present invention in an amount ranging from about 15 to about 35
weight percent and preferably from about 20 to about 25 weight
percent while the second high viscosity release retarding cellulose
ether can be present in the solid dosage forms of the present
invention in an amount ranging from about 5 to about 20 weight
percent and preferably from about 5 to about 15 weight percent.
[0024] The solid dosage forms of the present invention are orally
applicable single unit dosage forms. Examples of such dosage forms
include pills, capsules and tablets. Because of their ease in
administration, tablets represent the most advantageous oral solid
dosage form. Preferably, the tablet comprises one or more
additional pharmaceutically acceptable excipients other than the
release retarding cellulose ethers. Such excipients include
conventional pharmaceutical tablet excipients such as, for example
filler, binders, glidants, lubricants, pH modifying agents,
coloring agents, antioxidants, disintegrants, fillers and the like
and mixtures thereof. Suitable fillers include, but are not limited
to, sugar and sugar alcohols, and the like and mixtures thereof. A
preferred sugar is lactose and a preferred sugar alcohol is
mannitol. The lactose used in the compositions herein may be
lactose monohydrate or anhydrous lactose.
[0025] Suitable glidants include colloidal silicon dioxide, and the
like and mixtures thereof. Suitable lubricants include magnesium
stearate and the like and mixtures thereof.
[0026] Optionally the tablets of the present invention may be
colored with one or more coloring agents. Selection of coloring
agents can be made, for example, so that tablets of different
dosage strengths can be easily distinguished. Illustratively,
D&C Yellow #10 can be present in an amount of about 0.2 mg to
about 0.3 mg per tablet, and/or FD&C Blue #2 can be present in
an amount of about 0.05 mg to about 0.09 mg per tablet. In one
embodiment, D&C Yellow #10 and FD&C Blue #2 are used in
combination as a coloring agent.
[0027] The compositions of the present invention provide a release
rate of the one or more active pharmaceutical ingredients such as
alprazolam that is acceptable for once or twice daily dosing in
humans. Thus, the compositions of the present invention can be
orally administered in a therapeutically effective amount to a
human subject one or two times per day. The compositions of the
present invention can be used to treat any condition or disorder
that is responsive to benzodiazepine drugs, and are especially
useful in treatment or management of general anxiety disorder,
anxiety associated with depression, panic disorder and panic
attacks.
[0028] Another aspect of the present invention provides a method of
treating a CNS condition or disorder in a subject. The method
comprises orally administering to the subject a therapeutically
effective amount of a sustained-release pharmaceutical composition
as provided herein. The composition provides a release rate of the
active pharmaceutical ingredient such as alprazolam that is
acceptable for once or twice daily dosing in humans, thus in a
preferred method a composition of the invention is orally
administered in a therapeutically effective amount to a human
subject one or two times per day.
[0029] CNS conditions and disorders include those having a
neurologic and/or a psychiatric component. Illustrative CNS
conditions and disorders include, for example, personality
disorders including paranoid, schizoid, schizotypal, bipolar,
histrionic, delusional, narcissistic, emotionally unstable,
psychopathic and sociopathic personality disorders; habit and
impulse disorders including pathological gambling, stealing,
trichotillomania, etc.; obsessive-compulsive disorder;
passive-aggressive disorder; acute and transient psychotic
disorders; psychotic depression; schizoaffective disorder;
hypochondria; cyclothymia; dysthymia; manic-depressive illness;
major depressive disorder; treatment-resistant depression; adult
and childhood onset schizophrenias; drug dependence including
harmful use and abuse of, addiction to or dependence on opioids,
narcotics, barbiturates, alcohol, benzodiazepines, amphetamines,
cocaine, cannabinoids, hallucinogens, stimulants, nicotine
(tobacco) and solvents; withdrawal states and mood and psychotic
disorders related to such dependence; sexual dysfunction including
hypoactive sexual desire disorder, sexual aversion or avoidance and
erectile dysfunction; gender identity disorders; sexual preference
disorders; general anxiety disorder; social anxiety disorder; mixed
anxiety and depressive disorder; attention deficit hyperactivity
disorder (ADHD) and depression and anxiety associated therewith;
depression, anxiety, emotional dysregulation and behavioral
disturbances associated with mental retardation; developmental
disorders including autism, Asperger's syndrome and Rett's
syndrome; childhood conduct and attachment disorders; premenstrual
dysphoric disorder; postpartum depression; phobias including social
phobias, agoraphobia and specific phobias related for example to
hospitals, injections, venesection, etc.; posttraumatic stress
disorder; dissociative disorder; Briquet's syndrome; affective
disorders including depression, bipolar affective disorder and
recurrent depressive disorder; organic mood, anxiety and
emotionally labile disorders resulting for example from brain
damage or dysfunction arising from head injury, intracranial
masses, stroke, etc.; chronic fatigue; stress-induced psychotic
episodes; dementia including presenile dementia, Pick's disease,
vascular dementia, multi-infarct dementia, Alzheimer's disease,
dementia associated with Creutzfeldt-Jakob disease and HIV-related
dementia; other neurodegenerative disorders including Parkinson's
disease and Huntington's disease; suicidal behavior; eating
disorders including anorexia, bulimia and binge eating disorder;
adjustment disorders; somatization disorder; somatoform autonomic
dysfunction; somatoform pain disorder; panic attacks; panic
disorder; amnesia; neuropathic pain; fibromyalgia; migraine;
epilepsy; tinnitus; enuresis; sleep disorders including insomnia,
hypersomnia, narcolepsy, nightmares and night terrors; delirium;
postconcussion syndrome; multiple sclerosis; tremors; muscular
spasms; restless legs syndrome; Lennox-Gastaut syndrome; motor and
vocal tic disorders; Tourette's syndrome; supranuclear palsy;
Shy-Drager syndrome; trigeminal neuralgia; Bell's palsy; motor
neuron diseases such as amyotrophic lateral sclerosis; and
psychosomatic and psychosocial conditions associated with non-CNS
disorders such as diabetes, inflammatory disease, infertility,
allergies, psoriasis, asthma, hypertension, overactive bladder,
thyroid disorders, obesity, immune disorders and cancer.
[0030] The following examples are provided to enable one skilled in
the art to practice ntion and are merely illustrative of the
invention. The examples should not be read as the scope of the
invention as defined in the claims.
EXAMPLE 1
[0031] Tablets having the compositions shown in Table 1 were
prepared with an aoprazolam content of 0.5 mg, 1 mg, 2 mg and 3 mg,
respectively. TABLE-US-00001 TABLE 1 0.5 mg 1 mg 2 mg 3 mg Sr.
Qty/Tab Qty/Tab Qty/Tab Qty/Tab No. Ingredient (mg) (mg) (mg) (mg)
1 Alprazolam 0.50 1.00 2.00 3.00 2 Lactose monohydrate 147.50
146.80 145.80 144.60 (Pharmatose .RTM. 200M) 3 Hydroxypropyl 60.00
60.00 60.00 60.00 methylcellulose Substitution type 2910 (Methocel
.RTM. E4M) Viscosity by Ubbelhode 3000-5600 cps (nominal value 4000
cps) 4 Hydroxypropyl 28.00 28.00 28.00 28.00 methylcellulose
Substitution type 2208 (Methocel .RTM. K15M) Viscosity by Ubbelhode
11,250-21,000 cps (nominal value 15,000 cps) 5 Povidone K 25 8.00
8.00 8.00 8.00 6 D&C yellow No. 10 -- 0.20 -- 0.20 7 FD&C
blue No. 2 -- -- 0.20 0.20 Isopropyl alcohol (IPA) q.s q.s q.s q.s
8 Lactose Monohydrate 50.00 50.00 50.00 50.00 (Pharmatose .RTM. DCL
11) 9 Colloidal silicon dioxide 3.00 3.00 3.00 3.00 10 Magnesium
stearate 3.00 3.00 3.00 3.00 Total 300.00 300.00 300.00 300.00
Procedure
[0032] The alprazolam and ingredient numbers 2, 3, 4, 6 and 7 were
passed through an American Society for Testing and Materials (ASTM)
mesh 60# and mixed uniformly. Next, povidone was dissolved in
isopropyl alcohol (IPA) and the dry blend was granulated with IPA.
The wet mass was air dried in a fluid bed drier for 15 minutes and
then further dried at 55.degree. C. until the loss on drying (LOD)
was found to be less than 3%. The dried granules were sifted
through ASTM mesh # 30. The sifted granules were blended for 10
minutes with lactose monohydrate (Pharmatose DCL 11) and colloidal
silicon dioxide which were previously sifted through ASTM mesh #40.
The final lubrication was done for 5 minutes with magnesium
stearate, which was previously sifted through ASTM mesh # 80. The
lubricated granules were then compressed into tablets.
Testing
[0033] A study was conducted of the drug release of the 3 mg
alprazolam tablets of Example 1 compared to 3 mg alprazolam
Xanax.RTM. XR tablets (Pharmacia Corporation) in a dissolution bath
at 37.+-.0.5.degree. C. in 500 ml of a pH 6.0 Phosphate Buffer
using a U.S. Pharmacopoeia (USP) Type I apparatus with a basket
speed of 100 rpm for 18 hours. The results are set forth below in
Table 2. TABLE-US-00002 TABLE 2 Time Example 1 Xanax .RTM. XR
(Hours) (3 mg) Lot # 1 (3 mg) Lot # 2 (3 mg) 0.5 2 9 7 1 19 14 11 2
29 22 19 4 39 37 32 6 47 49 44 8 57 58 54 10 62 67 63 12 67 74 71
14 71 79 77 16 75 85 82
[0034] A study was also conducted of the drug release of the 3 mg
alprazolam tablets of Example 1 compared to 3 mg alprazolam
Xanax.RTM. XR tablets (Pharmacia Corporation) in a dissolution bath
at 37.+-.0.5.degree. C. in 500 ml of a pH 6.0 Phosphate Buffer
using a U.S. Pharmacopoeia (USP) Type I apparatus with a basket
speed of 100 rpm for two hours, then a dissolution bath at
37.+-.0.5.degree. C. in 500 ml of a 4.5 pH acetate buffer using a
USP Type I apparatus with a basket speed of 100 rpm for the next
two hours, and followed by dissolution bath at 37.+-.0.5.degree. C.
in 500 ml of a 6.8 pH phosphate buffer using a USP Type I apparatus
with a paddle speed of 100 rpm for the next 16 hours. The results
are set forth below in Table 3. TABLE-US-00003 TABLE 3 Xanax .RTM.
XR Time Example 1 Lot #1 Lot #1 (Hours) (3 mg) (3 mg) (3 mg) 0.1N
HCl 0.5 19 17 14 1 32 26 24 2 47 40 39 pH 4.5 Acetate 3 56 52 51
Buffer 4 59 54 53 pH 6.8 5 63 58 57 Phosphate 6 65 62 60 Buffer 8
69 71 69 10 73 80 77 12 76 87 84 14 80 92 89 16 83 95 93
EXAMPLE 2
[0035] Tablets having the composition shown in Table 4 were
prepared in substantially the same as in Example 1. TABLE-US-00004
TABLE 4 Qty/Tab INGREDIENTS (mg) Alprazolam 3.00 Pharmatose 200M
137.60 Hydroxypropyl methylcellulose 65.00 (Methocel .RTM. K4M CR)
Viscosity by Ubbelhode 3000-5600 cps (nominal value 4000 cps)
Hydroxypropyl methylcellulose 35.00 (Methocel .RTM. K15M) Viscosity
by Ubbelhode 11,250-21,000 cps (nominal value 15,000 cps) D&C
Yellow No. 10 0.20 FD&C Blue No. 2 0.20 Povidone K-25 3.00 IPA
Qs Pharmatose DCL 11 50.00 Aer-O-Sil 3.00 Magnesium Stearate 3.00
TOTAL 300.00
EXAMPLE 3
[0036] Tablets having the composition shown in Table 5 were
prepared in substantially the same manner as in Example 1.
TABLE-US-00005 TABLE 5 Qty/Tab INGREDIENTS (mg) Alprazolam 3.00
Pharmatose 200M 137.60 Hydroxypropyl methylcellulose 65.00
(Methocel .RTM. K4M CR) Viscosity by Ubbelhode 3000-5600 cps
(nominal value 4000 cps) Hydroxypropyl methylcellulose 35.00
(Methocel .RTM. E4M) Viscosity by Ubbelhode 3000-5600 cps (nominal
value 4000 cps) D&C Yellow No. 10 0.20 FD&C Blue No. 2 0.20
Povidone K-25 3.00 IPA Qs Pharmatose DCL 11 50.00 Aer-O-Sil 3.00
Magnesium Stearate 3.00 TOTAL 300.00
[0037] It will be understood that various modifications may be made
to the embodiments disclosed herein. Therefore the above
description should not be construed as limiting, but merely as
exemplifications of preferred embodiments. For example, the
functions described above and implemented as the best mode for
operating the present invention are for illustration purposes only.
Other arrangements and methods may be implemented by those skilled
in the art without departing from the scope and spirit of this
invention. Moreover, those skilled in the art will envision other
modifications within the scope and spirit of the features and
advantages appended hereto.
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